Cul4A is required for hematopoietic cell viability and its deficiency leads to apoptosis

David L. Waning, Binghui Li, Nan Jia, Yahaira Naaldijk, W. Goebel, Harm Hogeneseh, Kristin Chun

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

In vitro studies indicate that Cul4A ubiquitin ligases target for ubiquitin-mediated proteolysis regulators of cell-cycle progression, apoptosis, development, and DNA repair. In hematopoietic cell lines, studies by our group and others showed that Cul4A ligases regulate proliferation and differentiation in maturing myeloid and erythroid cells. In vivo, Cul4A-deficient embryos die in utero. Cul4A haploinsufficient mice are viable but have fewer erythroid and primitive myeloid progenitors. Yet, little more is known about Cul4A function in vivo. To examine Cul4A function in adults, we generated mice with interferon-inducible deletion of Cul4A. Cul4A deficiency resulted in DNA damage and apoptosis of rapidly dividing cells, and mutant mice died within 3 to 10 days after induction with dramatic atrophy of the intestinal villi, bone marrow, and spleen, and with hematopoietic failure. Cul4A deletion in vivo specifically increased cellular levels of the Cul4A ligase targets Cdt1 and p27 KlP1 but not other known targets. Bone marrow transplantation studies with Cul4A deletion in engrafted cells specifically isolated analysis of Cul4A function to hematopoietic cells and resulted in hematopoietic failure. These recipients died within 9 to 11 days, demonstrating that in hematopoietic cells, Cul4A is essential for survival.

Original languageEnglish
Pages (from-to)320-329
Number of pages10
JournalBlood
Volume112
Issue number2
DOIs
StatePublished - Jul 15 2008

Fingerprint

Ligases
Cell Survival
Cells
Apoptosis
Ubiquitin
Bone
Proteolysis
DNA
Interferons
Erythroid Cells
Repair
Myeloid Cells
Bone Marrow Transplantation
DNA Repair
DNA Damage
Atrophy
Cell Cycle
Spleen
Embryonic Structures
Bone Marrow

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Cul4A is required for hematopoietic cell viability and its deficiency leads to apoptosis. / Waning, David L.; Li, Binghui; Jia, Nan; Naaldijk, Yahaira; Goebel, W.; Hogeneseh, Harm; Chun, Kristin.

In: Blood, Vol. 112, No. 2, 15.07.2008, p. 320-329.

Research output: Contribution to journalArticle

Waning, David L. ; Li, Binghui ; Jia, Nan ; Naaldijk, Yahaira ; Goebel, W. ; Hogeneseh, Harm ; Chun, Kristin. / Cul4A is required for hematopoietic cell viability and its deficiency leads to apoptosis. In: Blood. 2008 ; Vol. 112, No. 2. pp. 320-329.
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